Michel Goedert

Goedert’s work combines biochemical, molecular biological and structural techniques to investigate common neurodegenerative diseases, including Alzheimer’s and Parkinson’s. In 1988, Goedert and colleagues reported that the microtubule-associated protein Tau is an integral component of the paired helical and straight filaments of Alzheimer’s disease. This led Goedert to clone, sequence and express in bacteria the six Tau isoforms that are produced in adult human brain and the big Tau isoform characteristic of the peripheral nervous system. In 1992, he reported that filaments from the brains of patients with Alzheimer’s disease contain all six Tau isoforms, each in a hyperphosphorylated state. In 1996, Goedert and colleagues showed that the addition of heparin leads to the assembly of non-phosphorylated recombinant Tau into filaments.

In 1998, Goedert and colleagues reported a mutation in MAPT, the Tau gene, that causes familial multiple system Tauopathy (the first use of that term) with presenile dementia, a familial form of frontotemporal dementia. Mutations in MAPT were also reported by others at the same time. Since then, Goedert and others identified additional pathogenic MAPT mutations (the current total stands at fifty-nine), which always lead to the formation of abundant filamentous Tau inclusions. Strikingly, these inclusions often resemble those of sporadic Tauopathies. The identification of MAPT mutations proved that dysfunction of Tau protein is sufficient to cause neurodegeneration and dementia. This work also resulted in the production, by Goedert and others, of mouse lines transgenic for human mutant Tau, that exhibit Tau hyperphosphorylation, filament formation and neurodegeneration. Using such lines, Goedert and colleagues showed that activation of autophagy can reduce seeded Tau aggregation and neurodegeneration.

In 2009, Goedert and colleagues demonstrated the prion-like behaviour of insoluble Tau in transgenic mouse brain. They subsequently showed that short Tau filaments constitute the major species of seed-competent protein in the brains of mice transgenic for human mutant Tau. In work using cultured cells, Goedert and colleagues showed that Tau aggregation is necessary for seeding and that conformation determines the potencies of native and recombinant Tau aggregates. In 2013, he and his colleagues reported that distinct human Tauopathies are probably caused by different molecular conformers of assembled Tau. The definition of a molecular conformer of assembled Tau must include its structural characterisation. In 2017, Goedert and colleagues reported the high-resolution structures of Tau filaments from Alzheimer’s disease, as determined by cryo-electron microscopy. This showed that high-resolution structures of amyloid filaments can be obtained using material purified from human brain. On-going work is aimed at determining the structures of Tau filaments from other Tauopathies, including Pick’s disease and progressive supranuclear palsy